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Reservoir-Membrane Systems

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Presentation on theme: "Reservoir-Membrane Systems"— Presentation transcript:

1 Reservoir-Membrane Systems
Controlled Release Reservoir-Membrane Systems

2 Overview History Membrane devices with constant release rate
Diffusion cell experiments with first order release Burst and lag effects in membrane systems Diffusion coefficients Membrane materials Applications of membrane systems

3 Components of membrane systems
Mechanism: diffusion-controlled Driving force: ΔC across membrane Medium: polymer membrane or liquid-filled pores Resistance: function of film thickness, diffusivity of solute in medium Membrane usually interfaces with biological site. Biocompatibility may be important.

4 History of Membrane Systems
Folkman and Long (1966 patent) Folkman studied effect of thyroid hormone on heart block Folkman needed non-inflammatory vehicle for extended release of hormone Long performed a photographic study of turbulence induced by artificial Si rubber heart valves Long noticed that certain dyes permeated Si rubber

5 History (continued) Folkman and Long tested diffusion of dyes and drugs across Si tube walls. Observed that oil-soluble, low MW (<1000) dyes permeated membrane Observed that water-soluble, high MW dyes did not. This was the beginning of a research EXPLOSION! First CR device (late 1960s) was use of hormones for contraception, which has now been widely studied.

6 Theory Fick’s First Law
membrane C1 C2 h Cm1 Cm2 C1<Cm1 the drug “prefers” the polymer Theory Fick’s First Law Relate Cm1 and Cm2 to surrounding concentrations Rewrite Flux Body acts as a sink (C2≈0) Constant rate can be achieved if C1 is kept constant.

7 What if C1 is not constant?
Common situation in diffusion cell Drug is depleted from reservoir (1) Drug accumulates in receiver (2) membrane C1 C2 h Cm1 Cm2

8 Diffusion cell: Derivation of M1(t)
Fick’s Law USS Mass Balance Combine USSMB with Fick’s Law Rearrange

9 Diffusion cell Integrate with IC: C1-C2= C10-C20 Apply mass balance

10 Diffusion cell Rearrange (see details)
Differentiate to find release rate First Order Release Rate Scan integration details on page 41a Check final result against published equaton.

11 Release profile for diffusion cell
Show two plots: M vs t and rate vs t

12 Data Analysis Diffusion Cell Experiment provides data for C1 vs t
Rearrange equation for M1 Taking natural log of both sides results in linearized eqn Scan rearrangement on yellow page

13 Graphing diffusion cell data
Experiment: L=2.5x10-3 cm V1=V2=3 cm3 A = 2 cm2 K = 1 (water-filled pores) Analysis m = s-1 m = Solve for D D=1.0 x 10-6 cm2/s

14 Burst and Lag Effects Previous analysis was based on steady-state flux in membrane membrane Cm1 C1 Cm2 C2 h

15 Burst and Lag Lag Burst membrane membrane C1 C1 Cm2 Cm1 Cm1 C2 Cm2 C2
h h Membrane exposed to reservoir at t=0 Initially no drug in membrane Takes time to build up SS concentration gradient Device stored before use Initial concentration of drug in membrane = C1 Takes time for drug to desorb and achieve SS concentration gradient

16 Lag Time & Burst Effect Equations for the amount of drug released after SS is attained in the membrane: Lag Burst Equations result from solving transport eqns. (Fick’s 2nd Law) for USS diffusion with relevant ICs; then taking limit as t →∞ These equations are for C1=const; C2=0

17 Burst and Lag Effects The lag time is the time required for the solute to appear on the receiver side. It is also the time required to attain a SS concentration profile in the membrane

18 Effect of lag and burst Membrane thickness 100 microns
D = 1 x cm2/s Calculate Lag time and Burst time Repeat for D = 1 x 10-9 cm2/s D = 1 x cm2/s D = 1 x 10-9 cm2/s tlag = 2.7 min tlag = 277 min tburst = 5.5 min tburst = 555 min

19 Diffusivity values for polymers
Function of MW Greater dependence for solute in polymers than for solute in liquids. For drugs with <400 MW In water: cm2/s<D<10-4 cm2/s Weak dependence on MW In rubbery polymer: cm2/s<D<10-4 cm2/s MW is somewhat important In glassy polymer: cm2/s<D<10-5 cm2/s Polymer is very stiff and rigid. Strong dependence on MW Insert graph of logD vs log MW

20 Diffusion through microporous membranes
Molecules move through liquid-filled pores Small molecules do not experience hindered diffusion Porosity 0 < ε <1 Tortuosity typically 1 < τ <5 pathlength is longer than membrane thickness

21 Membrane materials Silicone (Silastic – Dow Corning)
EVA – Ethylene Vinyl Acetate EVAc- Ethylene Vinyl Acetate copolymer Entrapped fluids Hydrogels and microporous membranes From Kydonieus

22 Silicone membranes Biocompatible and sterilizible
High permeability to many steroids Low permeability to ionized species Fick’s law is valid for many compounds D is on the order of 10-6 High compared to many polymers

23 Applications of Silicone membranes
5 year contraceptive Transderm Nitro patch: mg/cm2/day Applications from Robinson, p. 539

24 EVA Membrane Systems Advantages over silicone
Lower permeability to non-polar compounds offers better rate control Easier processing and formation of thermoplastic Extrusion, injection molding, film casting Co-polymers can effect big changes in properties Flexibility, permeability, strength

25 Examples of EVA Systems
Progestasert Progesterone contraceptive by ALZA Intrauterine device, 65 mcg per day for 400 days Silicone T-shaped tube with 35 mg drug in Si oil

26 Examples of EVA Systems
Ocusert Pilocarpine glaucoma treatment system by ALZA Thin, flexible “contacts” behind eyelid Use once a week; replaces drops 4 times per day Releases 20 or 40 mcg per hour Contains 5-11 mg pilocarpine Sterilized by irradiation Clear EVA membrane Opaque white sealing ring Pilocarpine reservoir Oval shape, 6 mm x 13 mm x 0.5 mm Thin EVA membranes 100 microns thick

27 Hydrogel systems Hydrophilic monomers that make cross-linked networks which hold water Great ease of synthesis Wide range of properties D depends on cross-linking agent and water content

28 Applications of hydrogels membrane systems
Fluoride salts in the mough 0.2 – 1.0 mg/day for 6 months Narcotic agonist – cyclazocine Prevents opiate effect and is used in rehabilitation Anticancer pouches for direct placement on tumors

29 Applications of microporous membranes
Microporous Membranes – used in many biomedical applications Blood oxygenation, dialysis, wound dressings, drug delivery Drug Delivery Applications Transderm Scop® (scopolamine) —Introduced in 1981 for motion-sickness. Microporous polypropylene membrane. (Alza-Ciba Geigy) Transderm-Nitro® (nitroglycerin) — For angina patients. Alternative to the brief effects of sublingual nitroglycerin and the messiness of nitroglycerin ointment. Microporous EVA membrane. (Alza-Ciba Geigy) Catapres-TTS® (clonidine) — Once-a week patch for hypertension replaces up to four daily oral doses. Uses microporous polypropylene membrane. (Alza-Boehringer/Ingelheim) Estraderm® (estradiol) —Twice-weekly, convenient estrogen replacement therapy. Avoids first pass and therefore uses only a fraction of the drug used in the oral therapy. Uses microporous polypropylene membrane. (Alze-Ciba Geigy) Duragesic® (fentanyl) —Introduced in 1991 for management of chronic pain via opioid analgesia. Uses microporous polyethylene membrane. (Alza) NicoDerm® CQ® (nicotine)—smoking-cessation aid in multiple dosage strengths offering maximum control of the drug delivery rate. Uses microporous polypropylene membrane. (Alza-GSK) Testoderm® and Testoderm® —Introduced in 1994 and 1998, respectively, for hormone replacement therapy in men with a deficiency or absence of testosterone. Microporous EVAc membrane. (Alza-Lederle)

30 ALZA’s Transderm Scop Removable strip Rate controlling microporous membrane with highly permeable liquid in pores Foil backing, protective and impermeable Adhesive gel layer with priming dose Reservoir with solid drug in highly permeable matrix Insert diagram of transdermal scop Controlled release form maintains low conc of drug, reduces side effects 2.5 cm2 area 200 mcg priming dose 10 mcg/h for 72 h steady state delivery

31 Diffusion Cell Equations
Derivation of M1(t)

32 Burst and Lag effects Ref. Kydonieus, A. Treatise on Controlled Drug Delivery

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